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      Molecular Screening of Small Biopsy Samples Using Next-Generation Sequencing in Korean Patients with Advanced Non-small Cell Lung Cancer: Korean Lung Cancer Consortium (KLCC-13-01)

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          Abstract

          Background

          Non-small cell lung cancer (NSCLC) is a common type of cancer with poor prognosis. As individual cancers exhibit unique mutation patterns, identifying and characterizing gene mutations in NSCLC might help predict patient outcomes and guide treatment. The aim of this study was to evaluate the clinical adequacy of molecular testing using next-generation sequencing (NGS) for small biopsy samples and characterize the mutational landscape of Korean patients with advanced NSCLC.

          Methods

          DNA was extracted from small biopsy samples of 162 patients with advanced NSCLC. Targeted NGS of genomic alterations was conducted using Ion AmpliSeq Cancer Hotspot Panel v2.

          Results

          The median age of patients was 64 years (range, 32 to 83 years) and the majority had stage IV NSCLC at the time of cancer diagnosis (90%). Among the 162 patients, 161 patients (99.4%) had novel or hotspot mutations (range, 1 to 21 mutated genes). Mutations were found in 41 genes. Three of the most frequently mutated genes were TP53 (151, 93.2%), KDR (104, 64.2%), and epidermal growth factor receptor (EGFR; 69, 42.6%). We also observed coexistence of EGFR and other oncogene (such as KRAS, PIC3CA, PTEN, and STK11) mutations. Given that 69.6% (48/69) of EGFR mutant patients were treated with EGFR tyrosine kinase inhibitors, EGFR mutant status had higher prognostic ability in this study.

          Conclusions

          These results suggest that targeted NGS using small biopsy samples is feasible and allows for the detection of both common and rare mutations in NSCLC.

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          Most cited references23

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          Acquired resistance to TKIs in solid tumours: learning from lung cancer.

          The use of advanced molecular profiling to direct the use of targeted therapy, such as tyrosine kinase inhibitors (TKIs) for patients with advanced-stage non-small-cell lung cancer (NSCLC), has revolutionized the treatment of this disease. However, acquired resistance, defined as progression after initial benefit, to targeted therapies inevitably occurs. This Review explores breakthroughs in the understanding and treatment of acquired resistance in NSCLC, focusing on EGFR mutant and ALK rearrangement-positive disease, which may be relevant across multiple different solid malignancies with oncogene-addicted subtypes. Mechanisms of acquired resistance may be pharmacological (that is, failure of delivery of the drug to its target) or biological, resulting from evolutionary selection on molecularly diverse tumours. A number of clinical approaches can maintain control of the disease in the acquired resistance setting, including the use of radiation to treat isolated areas of progression and adding or switching to cytotoxic chemotherapy. Furthermore, novel approaches that have already proven successful include the development of second-generation and third-generation inhibitors and the combination of some of these inhibitors with antibodies directed against the same target. With our increased understanding of the spectrum of acquired resistance, major changes in how we conduct clinical research in this setting are now underway.
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            KRAS mutations in lung cancer.

            Epidermal growth factor receptor (EGFR) gene mutations and increased EGFR copy numbers have been associated with a favorable response to EGFR tyrosine kinase inhibitors (TKI) in patients with non-small-cell lung cancer (NSCLC), and several markers have been identified that predict response to treatment. Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS), and mutations in EGFR and KRAS appear to be mutually exclusive. Even though KRAS mutations were identified in NSCLC tumors more than 20 years ago, we have only just begun to appreciate the clinical value of determining KRAS tumor status. Recent studies indicate that patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy and do not respond to EGFR inhibitors. There is a clear need for therapies specifically developed for patients with KRAS-mutant NSCLC. In this review, we summarize the clinical and pathologic characteristics of patients with NSCLC and with KRAS mutations, describe work that explores the predictive and prognostic influence of KRAS mutations, and provide an overview of the "synthetic lethal" interactions and current approaches to targeting KRAS-mutant NSCLC. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Overall survival benefits of first-line EGFR tyrosine kinase inhibitors in EGFR-mutated non-small-cell lung cancers: a systematic review and meta-analysis

              Background: Accumulating data shows that exon 19 deletions and L858R, both activating epidermal growth factor receptor mutations in non-small-cell lung cancers (NSCLCs), are just two different entities in terms of prognosis and treatment response to tyrosine kinase inhibitors (TKIs). Methods: A systematic review and meta-analysis of randomized controlled trials comparing TKIs with conventional chemotherapy was performed. Eight trials of 1498 patients and five trials of 1279 patients with either exon 19 deletions or L858R were included in the meta-analysis. Results: TKI treatment demonstrated progression-free survival benefit in patients with exon 19 deletions (hazard ratio (HR): 0.27, 95% confidence interval (CI): 0.21–0.35) and L858R (HR: 0.45, 95% CI: 0.35–0.58). Patients with exon 19 deletions had significant overall survival (OS) benefit under TKI treatment (HR: 0.72, 95% CI: 0.60–0.88). Subgroup analyses showed that irreversible TKIs, but not reversible TKIs, had statistically significant OS benefit in these patients (irreversible TKIs, HR: 0.59, 95% CI: 0.47–0.73; reversible TKIs, HR: 0.84, 95% CI: 0.69–1.02). Patients with L858R demonstrated no OS benefit under first-line TKI use (HR: 1.15, 95% CI: 0.95–1.39). Conclusions: In patients with advanced NSCLC harbouring exon 19 deletions, TKIs are associated with better OS compared with conventional chemotherapy. Future clinical trials should take exon 19 deletions and L858R as distinct disease entities and evaluate the treatment efficacy separately.
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                Author and article information

                Journal
                J Pathol Transl Med
                J Pathol Transl Med
                JPTM
                Journal of Pathology and Translational Medicine
                The Korean Society of Pathologists and the Korean Society for Cytopathology
                2383-7837
                2383-7845
                May 2018
                26 March 2018
                : 52
                : 3
                : 148-156
                Affiliations
                Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea
                [1 ]Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
                [2 ]CHA Bundang Medical Center, CHA University, Seongnam, Korea
                [3 ]Division of Medical Oncology, Yonsei Cancer Center, Seoul, Korea
                [4 ]Division of Hematology and Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
                [5 ]Division of Oncology, Department of Hematology and Oncology, Ulsan University Hospital, Ulsan, Korea
                [6 ]Division of Medical Oncology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
                [7 ]Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
                [8 ]Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
                Author notes
                Corresponding Author Kyung-Jong Lee, MD Division of Pulmonary and Clinical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-0777 Fax: +82-2-3410-6956 E-mail: kj2011.lee@ 123456samsung.com
                Myung-Ju Ahn, MD Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-3438 Fax: +82-2-3410-1754 E-mail: silk.ahn@ 123456samsung.com
                [*]

                Bo Mi Ku and Mi Hwa Heo contributed equally to this work.

                Article
                jptm-2018-03-12
                10.4132/jptm.2018.03.12
                5964289
                29575851
                10dbc560-07cf-46c5-afc7-b8568a7934f7
                © 2018 The Korean Society of Pathologists/The Korean Society for Cytopathology

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 December 2017
                : 26 February 2018
                : 12 March 2018
                Categories
                Original Article

                carcinoma, non-small cell lung,targeted next-generation sequencing,small biopsy,receptor, epidermal growth factor

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